Medulloblastoma is the most common malignant brain tumor of childhood. Survival rates for this disease remain poor and there is a great need for new treatment approaches. We previously demonstrated increased expression of ERBB2 oncogene in tumors from children with metastatic, poor prognosis disease. In preliminary data we now show that ERBB2 signaling in medulloblastoma cells promotes cell cycle progression and upregulates pro-metastatic and angiogenic genes. However, we also demonstrate that these effects may be reversed using small molecule inhibitors of ERBB2. In this project, three specific aims are proposed to establish the molecular and therapeutic significance of ERBB2 signaling in medulloblastoma. In aim 1 we will investigate the ability of ERBB2 signaling to promote tumor cell cycle progression, metastasis and invasion in human medulloblastoma cells engineered to express differential levels of ERBB2. Cells will be studied both in culture and as flank and CNS xenografts. We will also identify target genes of ERBB2 signaling, by conducting microarray analyses of these models and by comparing their expression-profiles to those of primary human medulloblastoma (n=45). In aim 2 we will use the models characterized in aim 1, to assess the efficacy of anti-ERBB2 novel therapies in medulloblastoma. The ability of three separate classes of ERBB2 inhibitor to abrogate ERBB2-dependent cell cycle progression, metastasis, angiogenesis and gene expression will be assessed. The use of these novel compounds will be optimized by parallel pharmacokinetic analyses that will also ensure accurate interpretation of pharmacodynamic effects. Finally, in aim 3 we will generate a transgenic mouse with ERBB2 overexpression targeted to the cerebellar external germinal layer. Using this model we will directly determine the ability of ERBB2 to induce malignant transformation in granule cell precursors. Particular attention will be focussed on the incidence, pathology and gene expression profile of developing tumors. Once characterized, this model will be employed in breeding experiments with mice bearing other medulloblastoma-specific genetic abnormalities eg., Ptc+/-. We will thereby investigate the ability of these defects to co-operate in medulloblastoma development and progression.